The present invention concerns (5E)-13,14,18,18,19,19-hexadehydro-3-oxa-6o-carbaprostaglandin I.sub.2 derivatives, the physiologically compatible salts thereof, a process for their preparation and their use as pharmaceuticals.
U.S. Pat. No. 4,423,067, whose disclosure is incorporated by reference herein, and corresponding German Unexamined Laid-Open Application 3,048,906.6, disclose carbacyclin derivatives of the formula ##STR2## wherein
R.sub.1 is OR.sub.2 wherein R.sub.2 is hydrogen, alkyl, cycloalkyl, aryl, or a heterocyclic residue; or is NHR.sub.3 wherein R.sub.3 is an acid residue or a hydrogen atom,
A is a --CH.sub.2 --CH.sub.2 --, trans--CH.dbd.CH--, or --C.tbd.C--group, PA0 W is a free or functionally modified hydroxymethylene group or a free or functionally modified ##STR3## wherein the OH-group can be in the .alpha.- or .beta.-position, D is a straight-chain or branched, saturated or unsaturated alkylene group of 1-10 carbon atoms which can optionally be substituted by fluorine atoms, 1,2-methylene or 1,1-trimethylene; PA0 E is a --C.tbd.C--bond or a --CR.sub.6 .dbd.CR.sub.7 -group wherein R.sub.6 and R.sub.7 are different from each other and are hydrogen or an alkyl group of 1-5 carbon atoms, PA0 R.sub.5 is C.sub.1-5 -alkyl, PA0 THP is tetrahydropyranyl, with a haloacetic acid derivative of Formula III ##STR7## wherein Hal is a chlorine, bromine, or iodine atom and PA0 R.sub.6 is C.sub.1-4 alkyl or trialkylsilyl with C.sub.1 C.sub.4 alkyl groups, or an alkali metal (Na, Li, K) cation, and, optionally, subsequently, in any desired sequence, conventionally separating isomers, saponifying esters, conventionally splitting off blocking groups, and, if desired, conventionally convertting the carboxy group into a physiologically compatible salt with a physiologically compatible base. PA0 R.sub.6 is an alkyl group of 1-5 carbon atoms.
R.sub.4 is an alkyl, cycloalkyl, or optionally substituted aryl group, or a heterocyclic group,
R.sub.5 is a free or functionally modified hydroxy group, and when R.sub.2 is hydrogen, the salts thereof with physiologically compatible bases
These compounds exhibit the properties typical for prostacyclins, such as, for example, lowering of peripheral arterial and coronary vascular resistance, inhibition of thrombocyte aggregation and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure without simultaneously lowering stroke volume and coronary blood flow; utilizability for treatment of stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, cardiac infarction, peripheral arterial diseases, arteriosclerosis and thrombosis, therapy for shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion, and cytoprotection for gastric and intestinal mucosa; antiallergic properties, lowering of pulmonary vascular resistance and pulmonary blood pressure, promotion of kidney blood flow, utilization in place of heparin or as an adjuvant in dialysis of hemofiltration, preservatron of blood plasma stores, especially blood platelet supplies, inhibition of labor, treatment of gestational toxicosis, enhancement of cerebral blood flow, etc. Furthermore, the novel prostaglandin analogs exhibit antiproliferative properties.
The nomenclature of these compounds is based on a proposal by Morton and Brokaw (J. Org. Chem. 44 : 2280 [1979]). Accordingly, (5E)-6a-carbaprostaglandin I.sub.2 has the following structural formula: ##STR4##